This application is to extend the NIMH Mid-Career Investigator Award in Patient-Oriented Research (K24) so that Dr. Malaspina may continue to successfully integrate research in the pathogenesis, treatment and prevention of schizophrenia with the training of junior investigators in translational neuroscience research. The receipt of this award produced a tripling of her research productivity, in addition to expanding her mentoring activity. She published a series of papers establishing advanced paternal age as a major risk factor for schizophrenia and demonstrated that olfactory processing and social capacity, known to be linked in other mammals, share common substrates in explaining the social deficits of schizophrenia, which are among its most disabling symptoms. This application includes a description of the candidate's success in research discoveries, funding, and the mentoring during the first 4 years of her current K24. With the extension of this support she will continue her commitment to a host of beginning clinical investigators. Her long-term goal is to establish herself as a leader in the etiology, heterogeneity and neurobiology of schizophrenia and psychosis vulnerability. The research objectives for this K24 renewal are to: (1) continue her currently funded studies to define risk factors for schizophrenia; (2) consolidate her skills and knowledge of epidemiologic and health services research methodologies, and develop collaborations with experts in preventive strategies to reduce schizophrenia's morbidity; and (3) successfully define key major unitary subtypes of schizophrenia from within the schizophrenia spectrum. Research projects which will serve as vehicles for achieving these objectives include efforts to resolve the heterogeneity of schizophrenia such that optimum treatment strategies may be devised. The mentorship objectives are (1) for the candidate to maintain her shift away from administrative and clinical duties (previously 50 percent of her time) so she may continue focus on mentoring junior investigators, (2) to attract trainees to schizophrenia research from a variety of health care disciplines (psychiatry, psychology, epidemiology, public health and others) and levels of training (students, residents, fellows, and junior faculty). The emphasis on individual genetic and environmental contributions to aspects of severe psychiatric diseases should lead to novel strategies for diagnosis, prevention, and treatment. It is expected that the results of these proposed clinical studies will provide new insights into the treatment of patients with specific subtypes of schizophrenia, as well as provide an excellent means whereby young investigators interested in patient-oriented translational research can be mentored and trained. [unreadable] [unreadable]